Infection with HIV often leads to the development of AIDS. This manifests with the development of opportunistic infections, many of which occur in the lung. The alveolar macrophage (AM) is the main resident inflammatory cell and defender of the lung against foreign antigens and microbes. Although AM are readily infected by HIV, the virus remains relatively dormant within these cells until late in the disease. The objective of this proposal is to examine the role C-C chemokines play in the regulation of HIV replication in AM. Preliminary data from our laboratory suggest that the C-C chemokines, especially RANTES, reduce HIV replication in peripheral blood monocytes (PBM) and AM. Whilst AM from subjects with asymptomatic HIV infection have increased capacity to synthesize these C-C chemokines, subjects with low CD4 counts with symptomatic lung disease demonstrate a reduced capacity. Our laboratory has demonstrated that C-C chemokine levels are regulated by arachidonic acid (AA) metabolites. Increases in prostaglandin (PG) and reduction in leukotrine (LT) synthesis in AM, which occurs with progression of HIV disease, may reduce C-C chemokine levels, and hence increase HIV replication. The hypothesis is that levels of C-C chemokines, especially RANTES, contribute to the regulation of HIV replication in AM. The specific aims of this proposal are (1) to determine if exogenous C-C chemokines regulate HIV replication in AM. In addition, (2) the role of endogenous C-C chemokines ina the regulation of HIV replication in AM will be examined. Furthermore, (3) the molecular mechanisms by which RANTES and other C-C chemokines regulate HIV replication will be studied. The experimental approach will be to study the effect of C-C chemokines on HIV infection in AM, PBM, ant the THP-1 monocytic cell line. AM will also be obtained from HIV-infected subjects. The effect of exogenous C-C chemokines on HIV replication will be explored. In addition, the role of endogenous C-C chemokines on HIV replication in AM will be examined by utilizing neutralizing antibodies and manipulating PG and LT levels. Molecular mechanisms of chemokine regulation of HIV replication including (1) blocking a shared receptor or (2) affecting transcriptional regulation will be investigated. In summary, this proposal will help determine the mechanisms by which HIV replication is regulated by C-C chemokines in AM, and enhance our understanding of and our ability to control HIV infection in the lung.